Brentuximab Vedotin and Combination Chemotherapy in Treating Patients With Stage II-IV HIV-Associated Hodgkin Lymphoma

HIV Infection Clinical Trial

Official title:

A Pilot Trial of AVD and Brentuximab Vedotin (SGN-35) in the Treatment of Stage II-IV HIV-Associated Hodgkin Lymphoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01771107
• Other study ID #: NCI-2013-00046
• Secondary ID: NCI-2013-0004620
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: March 7, 2013
• Est. completion date: February 28, 2025

Study information

• Verified date: April 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This pilot phase I/II trial studies the side effects and the best dose of brentuximab vedotin when given together with combination chemotherapy and to see how well they work in treating patients with stage II-IV human immunodeficiency virus (HIV)-associated Hodgkin lymphoma. Brentuximab vedotin is a monoclonal antibody, called brentuximab, linked to a chemotherapy drug called vedotin. Brentuximab attaches to CD30-positive cancer cells in a targeted way and delivers vedotin to kill them. Drugs used in chemotherapy, such as doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving brentuximab vedotin together with combination chemotherapy may kill more cancer cells.

Description:

PRIMARY OBJECTIVES I. To identify the maximum tolerated dose (MTD) of brentuximab vedotin when combined with the doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine (AVD) chemotherapy regimen in the treatment of HIV-associated stage II-IV Hodgkin lymphoma. (Phase I) II. Establish an estimate of the two-year progression-free survival (PFS) for participants with HIV-associated stage II-IV Hodgkin lymphoma when treated using brentuximab vedotin plus the AVD chemotherapy regimen. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of AVD and brentuximab vedotin with highly active antiretroviral therapy (HAART).

II. To estimate the partial response (PR) rate, complete response (CR) rate, overall survival (OS), and event free survival (EFS) at 2 and 5 years.

III. To evaluate the effect of AVD and brentuximab vedotin on cluster of differentiation (CD)4 and CD8 counts after cycle 1, 4, at the end of therapy, and every 3 months after treatment completion for one year.

IV. To investigate the prognostic value of fludeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans at baseline, after cycle 2, and at treatment completion, with respect to 2-year progression free survival.

V. To evaluate HAART status at baseline and to correlate this with tumor response to therapy and OS and PFS.

VI. To characterize the histologic subtypes in HIV-Hodgkin lymphoma (HL) in the highly active antiretroviral therapy (HAART) era.

VII. To assess the neurotoxicity of HAART in combination with AVD and brentuximab vedotin.

VIII. To evaluate effect of AVD and brentuximab vedotin on viral load after cycles 1, 4, at the completion of therapy, and every 3 months after treatment completion for one year.

IX. To perform pharmacokinetic and immunogenicity studies to determine drug levels during therapy.

X. To perform micro ribonucleic acid (miRNA) profile analysis on the HIV-HL tumor specimens and to correlate miRNA expression with OS, PFS, tumor response to therapy, histologic subtype of HIV-HL, and HIV disease characteristics.

XI. To perform tissue microarray analysis on HIV-HL tumor specimens and to correlate the markers studied with OS, PFS, and tumor response to therapy.

XII. To identify Epstein-Barr virus (EBV)-associated tumor derived deoxyribonucleic acid (DNA) in the plasma of study participants and to correlate these levels during therapy with disease response and OS. (Phase II) XIII. To identify cytokines in the plasma of participants during therapy that can be used as tumor and prognostic markers. (Phase II) XIV. To assess latent and expressed HIV reservoirs before, during, and post chemotherapy. To understand how cytotoxic chemotherapeutic agents affect HIV expression.

OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase II study.

Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine sulfate IV, and dacarbazine IV on days 1 and 15. Patients also receive brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Other known NCT identifiers

• NCT02298257

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 41
• Est. completion date: February 28, 2025
• Est. primary completion date: October 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• HIV positive; documentation of HIV-1 infection by means of any one of the following:

• Documentation of HIV diagnosis in the medical record by a licensed health care provider;

• Documentation of receipt of antiretroviral therapy (ART) by a licensed health care provider;

• HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNA copies/mL;

• Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 western blot confirmation or HIV rapid multispot antibody differentiation assay

• NOTE: A "licensed" assay refers to a United States (US) Food and Drug Administration (FDA)-approved assay, which is required for all investigational new drug (IND) studies

• Histologic diagnosis of CD30-positive classical HL as defined by the 2008 World Health Organization (WHO) Classification of Hematological diseases; nodular lymphocyte predominant Hodgkin lymphoma is not eligible

• Stage II, III or IV disease as defined by the Ann Arbor Staging System

• Participants must have previously untreated HIV-classical HL (cHL), with the exception of up to 14 consecutive days of steroids, emergency radiation, or 1 prior cycle of cyclophosphamide to reduce tumor burden and improve hyperbilirubinemia in the setting of lymphoma related liver involvement

• Normal baseline cardiac ejection fraction >= 50%

• Serum creatinine of =< 1.5 mg/dL; if creatinine > 1.5 mg/dL, creatinine clearance must be >= 60 mL/minute

• Absolute neutrophil count (ANC) >= 1000/uL

• Platelets >= 75,000/uL unless related to bone marrow involvement by HIV-cHL

• Total bilirubin must be < 1.5 x the upper limit of normal, unless the elevation of bilirubin is thought to be secondary to Gilbert's syndrome or combined antiretroviral therapy (cART); if, however, the elevated bilirubin is felt to be secondary to antiretroviral therapy, the total bilirubin must be =< 3.5 mg/dL, provided that the direct bilirubin is normal and the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x the upper limit of normal; also, if the elevated bilirubin is thought to be secondary to cHL the same criteria for hyperbilirubinemia should be applied; however 1 prior cycle of cyclophosphamide is permitted in attempt to make the participant eligible; patients should not be excluded from study participation unless dosing cannot be safely established

• Female participants must have a negative pregnancy test within 1 week of enrollment and all participants must agree to use two reliable methods of contraception simultaneously if conception is possible during the study and for 6 months after stopping treatment; should a woman subject become pregnant or suspect she is pregnant while the subject is participating in this study, she should inform her treating physician immediately; the participant will then be removed from protocol therapy; participants who father a child while participating in the study will be permitted to continue with the protocol; the participant, however, is required to notify the investigator if he fathers a child

• Ability to understand and the willingness to sign a written informed consent document

• Karnofsky performance status > 30% (given the aggressiveness of this disease and the often severely debilitated nature of the patients at initial presentation)

• Measurable or non-measurable (evaluable) tumor parameter(s); non-measurable tumor parameters will be defined as not having bi-dimensional measurements (i.e., gastric or marrow involvement) but can be followed for response by other diagnostic tests such as gallium, PET imaging and/or bone marrow biopsy

• Patients already receiving erythropoietin or granulocyte colony stimulating factor (GCSF) for treatment of HIV-related cytopenia are eligible

• CD4 count >= 50 cells/ul

• Participants are required to be on antiretroviral regimens that are in accordance with the current International Acquired Immune Deficiency Syndrome (AIDS) Society guidelines concurrently with chemotherapy; the specific agents are at the discretion of the investigator and the use of investigational agents currently available on an expanded access basis is allowed; use of experimental antiretroviral agents or those containing zidovudine (including Combivir and Trizivir) or ritonavir (includes Norvir or Kaletra), cobicistat, didanosine (Videx or Videx EC), or similar potent cytochrome P450 (CYP)3 inhibitors are prohibited; in order to be eligible, participants taking zidovudine or ritonavir, or cobicistat, didanosine, or other CYP3 inhibitors must change to a different regimen 7 days prior to therapy initiation; changes to HAART therapy during the study may be made if medically necessary (toxicity, failure of regimen, etc.); participants must be on HAART at least 7 days prior to therapy

• Negative for hepatitis B, or if infected with hepatitis B, receiving anti-hepatitis B therapy; all participants will be required to be screened for hepatitis B; per Infectious Disease Society of America (IDSA) and Assistance for AIDS Specific Drugs (AASD) guidelines, those participants that show no immunity, defined by the lack of hepatitis B surface antigen antibody, and show evidence of chronic infection (i.e. hepatitis B surface antigen [HBsAg]+, hepatitis B core [HBcore]+, hepatitis B surface antibody [HBsAB]-) will be required to be on anti-hepatitis B therapy during the study in order to be eligible; patients will be permitted to enroll in the study provided normal liver function tests and no evidence of cirrhosis; the exact hepatitis B therapy will be at the discretion of the infection disease specialist or investigator; however all patients who present with acute hepatitis B or show normal transaminases and are hepatitis B virus HBsAg surface protein antigen (HBsAg) positive (+) and immunoglobulin M (IgM)+ for hepatitis core antigen will not be eligible for trial enrollment

• Patients diagnosed with hepatitis C who are hepatitis C antibody positive, whether hepatitis C RNA level is measurable or not, must have no evidence of cirrhosis and have liver function tests

• Brentuximab vedotin is partially metabolized via the CYP3A4 pathway and is cleared from the cells via the P-glycoprotein pump; therefore, participants must discontinue use of the following agents within 7 days prior to therapy

• Strong CYP3A4 inhibitors that treat HIV

• Other strong CYP3A inhibitors

• Moderate CYP3A4 inhibitors should be used with caution but are not excluded; if 2 moderate CYP3A4 inhibitors are used concurrently, one must be discontinued at least 7 days (1 week) prior to the initiation of chemotherapy

• P-glycoprotein inhibitors

• If patients are taking any of these excluded medications, they must be discontinued at least 7 days (1 week) prior to the initiation of chemotherapy All concomitant medications must be reviewed by the study chair or co-chair prior to enrollment by email; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of

Exclusion Criteria:

• Patients with prior anthracycline therapy will be excluded

• Female participants who are pregnant or breast-feeding; confirmation that the subject is not pregnant must be established by a negative serum beta (b)-human chorionic gonadotropin (b-hCG) or urine pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women

• Medical illness unrelated to HL, which in the opinion of the study physician will preclude administration of chemotherapy safely; this includes patients with uncontrolled infection (including opportunistic), chronic renal failure, myocardial infarction (MI) within the past 6 months, unstable angina, or cardiac arrhythmias other than chronic atrial fibrillation, or second malignancy requiring active treatment

• Prior malignancy within 2 years before enrollment other than curatively treated cutaneous basal cell or squamous cell carcinoma, carcinoma in situ of the cervix, anal intraepithelial neoplasia, or cutaneous Kaposi's sarcoma (KS); participants with prior malignancies must have completed all therapy at least 2 years before enrollment with no evidence of disease since therapy completion

• Grade 2 or greater peripheral neuropathy

• Evidence of progressive multifocal leukoencephalopathy (PML) identified on the pretreatment magnetic resonance imaging (MRI)

• Central nervous system disease

• Patients with history of John Cunningham (JC) virus identified in the cerebrospinal fluid (CSF) or previous history of PML will be excluded from the study

• Cirrhosis secondary to any cause will be excluded

Related Conditions & MeSH terms

• AIDS-Related Hodgkin Lymphoma
• Ann Arbor Stage II Hodgkin Lymphoma
• Ann Arbor Stage IIA Hodgkin Lymphoma
• Ann Arbor Stage IIB Hodgkin Lymphoma
• Ann Arbor Stage III Hodgkin Lymphoma
• Ann Arbor Stage IIIA Hodgkin Lymphoma
• Ann Arbor Stage IIIB Hodgkin Lymphoma
• Ann Arbor Stage IV Hodgkin Lymphoma
• Ann Arbor Stage IVA Hodgkin Lymphoma
• Ann Arbor Stage IVB Hodgkin Lymphoma
• Classic Hodgkin Lymphoma
• HIV Infection
• Hodgkin Disease
• Lymphoma

Intervention

Drug:
• Brentuximab Vedotin
Given IV
• Dacarbazine
Given IV
• Doxorubicin Hydrochloride
Given IV

Other:
• Pharmacological Study
Correlative studies

Drug:
• Vinblastine
Given IV

Locations

Country	Name	City	State
France	Centre Hospitalier Universitaire (CHU) de Toulouse	Cedex
France	Hopital Antoine Beclere	Clamart
France	Henri Mondor University-Hospital Center	Creteil
France	Hopital l'Archet-CHU de Nice	Nice
France	Hopital Saint Louis	Paris
France	Hospital Saint-Antoine	Paris
France	Centre Hospitalier Lyon-Sud	Pierre Benite
France	Chu Purpan	Toulouse
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California
United States	UCLA Center for Clinical AIDS Research and Education	Los Angeles	California
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Louisiana State University Health Science Center	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Siteman Cancer Center at Washington University	Saint Louis	Missouri
United States	Washington University - Jewish	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Harborview Medical Center	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	The Lymphoma Academic Research Organisation

Countries where clinical trial is conducted

United States,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximal Tolerated Dose of Brentuximab Vedotin (Phase I)	Defined as the dose level at which =< 1 of 6 subjects experience dose limiting toxicity.	28 days
Primary	2-year Progression-free Survival (PFS)	2-year PFS is determined based on the Kaplan-Meier estimates and corresponding 95% confidence intervals based on standard errors using Greenwood's formula.	2 years
Secondary	Frequency of Adverse Events	Number of Participants who had one or more adverse events	Up to 5 years
Secondary	Partial Response Rate	Number of participants who achieved a partial response per RECIST v1.0 criteria	2 years
Secondary	Partial Response Rate	Number of participants who achieved a partial response per RECIST v1.0 criteria	5 years
Secondary	Complete Response Rate	Number of participants who experienced a complete response per RECIST v1.0 criteria	2 years
Secondary	Complete Response Rate	Number of participants who achieved a complete response per RECIST v1.0 criteria	5 years
Secondary	2-year Overall Survival	Proportion of study participants who are alive at 2 years estimated using the Kaplan-Meier survival function	2 years
Secondary	Overall Survival	Proportion of participants who are alive at 5 years using a Kaplan-Meier estimate	5 years
Secondary	Event-free Survival	Proportion of participants who are alive and progression-free at 2 years	2 years
Secondary	Event-free Survival	Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates (i.e., partial response rate, complete response rate, overall response rate) and event free survival at 2 and 5 years of AVD and brentuximab vedotin for a treatment of patients with stage III/IV HIV-associated Hodgkin lymphoma.	5 years
Secondary	CD4 Counts	CD4 counts (absolute) at visit 4 (cycle 5)	5 months
Secondary	CD8 Counts	Absolute CD8 counts at cycle 5	5 months
Secondary	Viral Load	HIV viral load (detectable)	5 months
Secondary	Prognostic Value of Fludeoxyglucose F-18 (FDG)-Positron Emission Tomography (PET) in Patient With HIV and Hodgkin Lymphoma (HL) With Respect to 2 Year Progression Free Survival	Log-rank analysis will be used to investigate the prognostic value of FDG-PET scans at baseline, after 2 courses and post-therapy in patients with HIV and HL with respect to progression free survival.	Baseline
Secondary	Prognostic Value of FDG-PET in Patient With HIV and HL With Respect to 2 Year Progression Free Survival	Log-rank analysis will be used to investigate the prognostic value of FDG-PET scans at baseline, after 2 courses and post-therapy in patients with HIV and HL with respect to progression free survival.	8 weeks (after 2 courses)
Secondary	Prognostic Value of FDG-PET in Patient With HIV and HL With Respect to 2 Year Progression Free Survival	Log-rank analysis will be used to investigate the prognostic value of FDG-PET scans at baseline, after 2 courses and post-therapy in patients with HIV and HL with respect to progression free survival.	24 weeks (end of treatment)
Secondary	HAART Status	Log-rank analysis will be used to evaluate HAART status at baseline for difference in outcome in terms of overall survival and progression free survival.	Baseline
Secondary	Characterization of Histologic Subtypes in HIV-HL in the HAART Era	Participants with mixed cellularity histologic subtype	Baseline
Secondary	Incidence of Neurotoxicity	Number of participants who experience neurotoxicity at cycle 5 (visit 4)	5 months